The signaling pathway of epidermal growth factor receptor (EGFR), a cell membrane bound tyrosine kinase, plays an important role in breast cancer progression and regulates cell metabolism through kinasedependent and -independent mechanism. Additionally, accumulated evidence has demonstrated the close relationship between cancer progression and energy metabolism. Metabolic deregulation has even lately been considered as the seventh hallmark of cancers in addition to the well-established six hallmarks. Recently, we have demonstrated that EGFR, independent of its kinase activity, maintains the basal intracellular glucose level by associating with and stabilizing a sodium/glucose cotransporter (SGLT1), thereby preventing cells from undergoing autophagic death. The resulL together with those reported in the literature that AKT may activate another glucose transporter, GLLIT4 to enhance energy metabolism had stimulated us to hypothesize that EGFR may mediate glucose uptake through both tyrosine kinase dependent and independent pathways, which may contribute to the EGFR-mediated malignant phenotype in breast cancer cells. In addition, we and others have also shown that cell surface receptor-mediated kinases including ERK, AKT and IKK regulate TSC1/TSC2 complex and FoxoSa, both of which are known to involve in tumor progression and energy balance. These three kinases are frequently activated in human cancers including breast cancer and have served as therapeutic targets for the development on anti-cancer drugs. The long-term goal of this proposal is to understand molecular mechanism of breast cancer progression and metabolic regulation. Specifically, in the current proposal we propose three Specific Aims to fulfill the goals: Specific Aim 1: To elucidate the role of kinase-independent EGFR mediated glucose transporter signaling in mammary tumor progression. Specific Aim 2: To investigate energy metabolism regulated by the kinase-dependent EGFR signaling pathways. Specific Aim 3: To determine the role of kinase-dependent EGFR signaling in mammary tumor progression. The outcome of this project will advance an understanding on the effect of glucose metabolism on breast cancer progression and may shed light on new directions for breast cancer therapy.